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Late Effects of Treatment for Childhood Cancer (PDQ®)

Late Effects of the Digestive System

Dental

Overview

Chemotherapy, radiation therapy, and local surgery can cause multiple cosmetic and functional abnormalities of the oral cavity and dentition. The quality of current evidence regarding this outcome is limited by retrospective data collection, small sample size, cohort selection and participation bias, and heterogeneity in treatment approach, time since treatment, and method of ascertainment.

Oral and dental complications reported in childhood cancer survivors include the following:

Abnormalities of tooth development

Abnormalities of dental development reported in childhood cancer survivors include absence of tooth development, hypodontia, microdontia, enamel hypoplasia, and root malformation.[1-9] The prevalence of hypodontia has varied widely in series depending on age at diagnosis, treatment modality, and method of ascertainment. Cancer treatments that have been associated with dental maldevelopment include head and neck radiation, any chemotherapy, and hematopoietic stem cell transplantation (HSCT). Children younger than 5 years are at greatest risk for dental anomalies, such as root agenesis, delayed eruption, enamel defects, and/or excessive caries related to disruption of ameloblast (enamel producing) and odontoblast (dentin producing) activity early in life.[3]

Key findings related to cancer treatment effect on tooth development include the following:

Radiation directed at oral cavity or surrounding structures increases the risk of dental anomalies because ameloblasts can be permanently damaged by doses as low as 10 Gy.[3,5,6,10] However, the most significant degree of tooth aplasia or delayed eruption occurs in younger children (aged <4 years) who are exposed to radiation doses of 20 Gy or higher.[11] Developing teeth may be irradiated in the course of treating head and neck sarcomas, Hodgkin lymphoma, neuroblastoma, central nervous system leukemia, nasopharyngeal cancer, and as a component of total-body irradiation (TBI). Doses of 10 Gy to 40 Gy can cause root shortening or abnormal curvature, dwarfism, and hypocalcification.[12] Significant dental abnormalities, including mandibular or maxillary hypoplasia, increased caries, hypodontia, microdontia, root stunting, and xerostomia have been reported in more than 85% of survivors of head and neck rhabdomyosarcoma treated with radiation doses greater than 40 Gy.[4,5]

Chemotherapy, especially exposure to alkylating agents, can affect tooth development.[3,6,7] Chemotherapy for the treatment of leukemia can cause shortening and thinning of the premolar roots and enamel abnormalities.[13-15] Childhood Cancer Survivor Study (CCSS) investigators identified age younger than 5 years and increased exposure to cyclophosphamide as significant risk factors for developmental dental abnormalities in long-term survivors of childhood cancer.[3]

HSCT conditioning, especially regimens containing TBI, may result in tooth agenesis and root malformation. Younger children who have not developed secondary teeth are most vulnerable.[1,2,6] Children who undergo HSCT with TBI may develop short V-shaped roots, microdontia, enamel hypoplasia, and/or premature apical closure.[1,2,8] The younger a patient is when treated with HSCT, the more severely disturbed dental development will be and the more deficient vertical growth of the lower face will be. These high-risk patients require close surveillance and appropriate interventions.[9]

Salivary gland dysfunction

Xerostomia, the sensation of dry mouth, is a potential side effect following head and neck irradiation or HSCT that can severely impact quality of life. Complications of reduced salivary secretion include increased caries, susceptibility to oral infections, sleep disturbances, and difficulties with chewing, swallowing, and speaking.[16,17] The prevalence of salivary gland dysfunction after cancer treatment varies based on measurement techniques (patient report vs. stimulated or unstimulated salivary secretion rates).[18] In general, the prevalence of self-reported persistent posttherapy xerostomia is infrequent among childhood cancer survivors. In the CCSS, the prevalence of self-reported xerostomia in survivors was 2.8 % compared with 0.3% in siblings, with an increased risk in survivors older than 30 years.[3]

Salivary gland irradiation incidental to treatment of head and neck malignancies or Hodgkin lymphoma causes a qualitative and quantitative change in salivary flow, which can be reversible after doses of less than 40 Gy but may be irreversible after higher doses, depending on whether sensitizing chemotherapy is also administered.[16]

The association of chemotherapy alone with xerostomia remains controversial.[16] Only one study of pediatric patients demonstrated an excess risk (odds ratio, 12.32 [2.1–74.4]) of decreased stimulated saliva flow rates among patients treated with cyclophosphamide; however, no increased dental caries were noted and patient-reported xerostomia was not evaluated.[7]

HSCT recipients are at increased risk of salivary gland dysfunction related to transplant conditioning or graft-versus-host disease (GVHD). GVHD can cause hyposalivation and xerostomia with resultant dental disease. In a study of pediatric HSCT survivors, 60% of those exposed to a conditioning regimen with cyclophosphamide and 10 Gy single-dose TBI had decreased salivary secretion rates, compared with 26% in those who received cyclophosphamide and busulfan.[19] In contrast, in another study, the prevalence of reduced salivary secretion did not differ among long-term survivors based on conditioning regimen (single-dose TBI, 47%; fractionated TBI, 47%; busulfan, 42%).[20]

The impact of infectious complications and alterations in the microflora during and after therapy is not known.[6]

Abnormalities of craniofacial development

Craniofacial maldevelopment is a common adverse outcome among children treated with high-dose radiation therapy to the head and neck that frequently occurs in association with other oral cavity sequelae such as dental anomalies, xerostomia, and trismus.[5,21,22] The extent and severity of musculoskeletal disfigurement is related to age at treatment and radiation therapy volume and dose, with higher risk observed among younger patients and those who received 30 Gy or more. Remediation of cosmetic and functional abnormalities often requires multiple surgical interventions.

Posttherapy management

Some studies suggest there may be a benefit of fluoride products or chlorhexidine rinses in patients who have undergone radiation.[23] Dental caries are a problematic consequence of reduced salivary quality and flow. The use of topical fluoride can dramatically reduce the frequency of caries, and saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia.[17]

It has been reported that the incidence of dental visits for childhood cancer survivors falls below the American Dental Association's recommendation that all adults visit the dentist annually.[24] The Children’s Oncology Group Long-term Follow-Up Guidelines recommend biannual dental cleaning and exams for all survivors of childhood cancer. These findings give health care providers further impetus to encourage routine dental care and dental hygiene evaluations for survivors of childhood treatment. (Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information about oral complications in cancer patients.)

Digestive Tract

Overview

The gastrointestinal (GI) tract is sensitive to the acute toxicities of chemotherapy, radiation, and surgery. However, these important treatment modalities can also result in some long-term issues in a treatment- and dose-dependent manner. Reports published about long-term GI tract outcomes are limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment.

Key concepts about GI complications observed in childhood cancer survivors include the following:

Treatment-related late effects include the following:

Cancer and its therapy can increase the risk of upper and lower digestive tract late effects.

Dose intensity of chemotherapy and use of abdominal irradiation influences the risk of digestive tract late effects.

Another cohort study of children treated for acute myeloid leukemia with chemotherapy alone found that reported GI disorders were relatively rare and not significantly different from those reported by sibling controls.[26]

Late radiation injury to the digestive tract is attributable to vascular injury. Necrosis, ulceration, stenosis, or perforation can occur and are characterized by malabsorption, pain, and recurrent episodes of bowel obstruction, as well as perforation and infection.[27-29] In general, fractionated doses of 20 Gy to 30 Gy can be delivered to the small bowel without significant long-term morbidity. Doses greater than 40 Gy cause bowel obstruction or chronic enterocolitis.[30] Sensitizing chemotherapeutic agents such as dactinomycin or anthracyclines can increase this risk.

A limited number of reports describe GI complications in pediatric patients with genitourinary solid tumors treated with radiation:[31-35]

One study comprehensively evaluated intestinal symptoms in 44 children with cancer who underwent whole-abdominal (10–40 Gy) and involved-field (25–40 Gy) radiation and received additional interventions predisposing them to GI tract complications including abdominal laparotomy in 43 patients (98%) and chemotherapy in 25 patients (57%).[31] Late small-bowel obstruction was observed in 36% of patients surviving for 19 months to 7 years, which was uniformly preceded by small bowel toxicity during therapy.

Reports from the Intergroup Rhabdomyosarcoma Study evaluating GI toxicity in long-term survivors of genitourinary rhabdomyosarcoma infrequently observed abnormalities of the irradiated bowel.[32,33,35] Radiation-related complications occurred in approximately 10% of long-term survivors of paratesticular and bladder/prostate rhabdomyosarcoma and included intraperitoneal adhesions with bowel obstruction, chronic diarrhea, and stricture or enteric fistula formation.[32,35]

Children irradiated at lower doses for Wilms tumor also uncommonly develop chronic GI toxicity. Several studies have reported cases of small bowel obstruction after abdominal surgery, but the role of radiation appears to be less important as operative findings of enteritis have not consistently been observed.[34,36]

Another study evaluated the risk of small bowel obstruction in patients diagnosed with intra-abdominal malignancies at a single institution.[37] Eleven of 291 patients (3.8%) developed small bowel obstruction with a mean follow-up of 3.6 years. Wilms tumor, rhabdomyosarcoma, and Burkitt lymphoma appeared to be associated with a higher risk.

Children with primary liver tumors requiring significant lever resection, or even transplant, are at higher risk for liver injury.

Children receiving irradiation to the liver are at higher risk for liver injury.

Children undergoing bone marrow transplant are at higher risk for liver injury.

Certain factors, including the type of chemotherapy, the dose and extent of radiation exposure, the influence of surgical interventions, and the evolving impact of viral hepatitis and/or other infectious complication, need additional attention in future studies.

Types of hepatobiliary complications

Asymptomatic elevations of blood biomarkers. Blood biomarkers include the following: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT). Liver injury related to treatment for childhood cancer is often asymptomatic and indolent in course. Dutch investigators observed hepatobiliary dysfunction in 8.7% of 1,362 long-term survivors (12.4 years of median follow-up since diagnosis) evaluated by ALT for hepatocellular injury and GGT for biliary tract injury. Cases with a history of viral hepatitis and a history of veno-occlusive disease were excluded. Predictors for elevated ALT and GGT by multivariable analysis included treatment with radiation therapy involving the liver, higher body mass index (BMI), higher alcohol intake, and longer follow-up time; older age at diagnosis was only signiﬁcantly associated with elevated GGT levels.[39] In a CCSS report, survivors of childhood cancer were more than two times more likely to report a hepatic-related health issue and were nearly nine times more likely to report cirrhosis, compared with sibling controls.[25]

Less commonly reported hepatobiliary complications include the following:

Cholelithiasis. In limited studies, an increased risk of cholelithiasis has been linked to ileal conduit, parenteral nutrition, abdominal surgery, abdominal radiation, and HSCT.[40,41] Gallbladder disease was the most frequent late-onset liver condition reported among participants in the CCSS, and they had a twofold excess risk compared with sibling controls (RR, 2.0; 95% CI, 2.0–40.0).[25]

Focal nodular hyperplasia. Lesions made up of regenerating liver called focal nodular hyperplasia have been incidentally noted after chemotherapy or HSCT.[42,43] These lesions are thought to be iatrogenic manifestations of vascular damage and have been associated with veno-occlusive disease, high-dose alkylating agents (e.g., busulfan and melphalan), and liver irradiation. The
prevalence of this finding is unknown; while noted at less than 1% in some papers,[43] this is likely an underestimate. In one study of patients who were followed by magnetic resonance imaging (MRI) after transplant to assess liver iron stores, the cumulative incidence was 35% at 150 months posttransplant.[42] The lesions can mimic metastatic or subsequent tumors, but MRI imaging is generally diagnostic, and unless the lesions grow or patients have worrisome symptoms, biopsy or resection is generally not necessary.

Nodular regenerative hyperplasia. Nodular
regenerative hyperplasia is a rare condition characterized by the development of multiple monoacinar regenerative hepatic nodules and mild fibrosis. The pathogenesis is not well established but may represent a nonspecific tissue adaptation to heterogeneous hepatic blood flow.[44]
Nodular
regenerative hyperplasia has rarely been observed in survivors of childhood cancer treated with chemotherapy, with or without liver irradiation.[45,46] Biopsy may be necessary to distinguish nodular
regenerative hyperplasia from a subsequent malignancy.

Microvesicular fatty change. In a cohort who recently completed intensified therapy for acute lymphoblastic leukemia, histologic evidence of fatty infiltration was noted in 93% and siderosis in up to 70% of patients.[47] Fibrosis developed in 11% and was associated with higher serum low-density lipoprotein (LDL) cholesterol. Fatty liver with insulin resistance has also been reported to develop more frequently in long-term childhood cancer survivors treated with cranial irradiation before allogeneic stem cell transplantation who were not overweight or obese.[48] Prospective studies are needed to define whether acute posttherapy fatty liver change contributes to the development of steatohepatitis or the metabolic syndrome in this population.

Transfusion-related iron overload. Red blood cell transfusions can result in an accumulation of excess iron due to disruption of the homeostasis of iron storage and distribution when exogenous iron is loaded into organs. Transfusional iron overload has been reported in pediatric oncology patients, but its prevalence, organ distribution, and severity remain incompletely characterized. MRI has emerged as an accurate, noninvasive means for measuring iron in multiple organ systems.[49,50] In a cross-sectional study of 75 patients (4.4 years of median follow-up time; 4.9 years since last transfusion), MRI iron concentrations were elevated in the liver (49.3%) and pancreas (26.4%), but not in the heart. In a multivariable analysis, cumulative packed red blood cell volume and older age at diagnosis predicted elevated liver iron concentration.[49] Further research is needed to better characterize survivors at risk of clinically significant transfusion-related iron overload who may benefit from interventions to reduce iron loading and organ dysfunction.

Treatment-related risk factors for hepatobiliary complications

The type and intensity of previous therapy influences risk for late-occurring hepatobiliary complications. In addition to the risk of treatment-related toxicity, recipients of HSCT frequently experience chronic liver dysfunction related to microvascular, immunologic, infectious, metabolic, and other toxic etiologies.

Chemotherapy. Chemotherapeutic agents with established hepatotoxic potential include antimetabolite agents like 6-mercaptopurine, 6-thioguanine, methotrexate, and rarely, dactinomycin. Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) and cholestatic disease have been observed after thiopurine administration, especially 6-thioguanine. Progressive fibrosis and portal hypertension has been reported in a subset of children who developed VOD/SOS after treatment with 6-thioguanine.[51-53] Acute, dose-related, reversible VOD/SOS has been observed in children treated with dactinomycin for pediatric solid tumors.[54,55]

In the transplant setting, VOD/SOS has also been observed after conditioning regimens that have included cyclophosphamide/TBI, busulfan/cyclophosphamide and carmustine/cyclophosphamide/etoposide.[56] Because high-dose cyclophosphamide is common to all of these regimens, toxic cyclophosphamide metabolites resulting from the agent’s variable metabolism have been speculated as a causative factor.

Radiation therapy. Acute radiation-induced liver disease also causes endothelial cell injury that is characteristic of VOD/SOS.[57] In adults, the whole liver has tolerance up to 30 Gy to 35 Gy with conventional fractionation, the prevalence of radiation-induced liver disease varies from 6% to 66% based on the volume of liver involved and on hepatic reserve.[57,58]

Based on limited data from pediatric cohorts treated in the 1970s and 1980s, persistent radiation hepatopathy after contemporary treatment appears to be uncommon in long-term survivors without predisposing conditions such as viral hepatitis or iron overload.[59] The risk of injury in children increases with radiation dose, hepatic volume, younger age at treatment, previous partial hepatectomy, and concomitant use of radiomimetic chemotherapy like dactinomycin and doxorubicin.[60-63] Survivors who received radiation doses of 40 Gy to at least one-third of liver volume, doses of 30 Gy or more to whole abdomen, or an upper abdominal field involving the entire liver are at highest risk for hepatic dysfunction.[64]

Hematopoietic stem cell transplantation. Chronic liver dysfunction in patients undergoing HSCT is multifactorial in etiology. The most common etiologies for chronic liver dysfunction include iron overload, chronic GVHD, and viral hepatitis.[65] Patients with chronic GVHD of the GI tract who exhibit an elevated bilirubin have a worse prognosis and quality of life.[66] While chronic liver dysfunction may be seen in more than half of long-term stem cell transplantation survivors, the course of the disease is mild and indolent in most patients.[67]

Infectious risk factors for hepatobiliary complications

Viral hepatitis B and C may complicate the treatment course of childhood cancer and result in chronic hepatic dysfunction. Hepatitis B tends to have a more aggressive acute clinical course and a lower rate of chronic infection. Hepatitis C is characterized by a mild acute infection and a high rate of chronic infection. The incidence of transfusion-related hepatitis C in childhood cancer survivors has ranged from 5% to 50% depending on the geographic location of the reporting center.[68-74]

Chronic hepatitis predisposes the childhood cancer survivor to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Concurrent infection with both viruses accelerates the progression of liver disease. Because most patients received some type of blood product during childhood cancer treatment and many are unaware of their transfusion history, screening based on date of diagnosis/treatment is recommended unless there is absolute certainty that the patient did not receive any blood or blood products.[75] Therefore, all children who received blood transfusions before 1972 should be screened for hepatitis B, and all children who received blood transfusions before 1993 should be screened for hepatitis C and referred for discussion of treatment options.

Posttherapy management

Survivors with liver dysfunction should be counseled regarding risk-reduction methods to prevent hepatic injury. Standard recommendations include maintenance of a healthy body weight, abstinence from alcohol use, and immunization against hepatitis A and B viruses. In patients with chronic hepatitis, precautions to reduce viral transmission to household and sexual contacts should also be reviewed.

Pancreas

The pancreas has been thought to be relatively radioresistant because of a paucity of information about late pancreatic-related effects. However, children and young adults treated with TBI or abdominal irradiation are known to have an increased risk of insulin resistance and diabetes mellitus.[76-78]

A summary of the results of selected cancer cohort studies supporting this association include the following:

A retrospective cohort study, based on self-reports of 2,520 5-year survivors of childhood cancer treated in France and the United Kingdom, investigated the relationship between radiation dose to the pancreas and risk of a subsequent diabetes mellitus diagnosis. Sixty-five cases of diabetes mellitus were validated; the risk increased with radiation to the tail of the pancreas, where the islets of Langerhans are concentrated. Risk increased up to 20 to 29 Gy and then plateaued. The estimated RR at 1 Gy was 1.61. Radiation dose to other parts of the pancreas did not have a significant effect. Compared with patients who did not receive radiation, the RR of diabetes mellitus was 11.5 in patients who received more than 10 Gy to the pancreas. Children younger than 2 years at the time of radiation were more sensitive than were older patients (RR at 1 Gy was 2.1 for the young age group vs. 1.4 for older patients). For the 511 patients who received more than 10 Gy, the cumulative incidence of diabetes mellitus was 16%.[79]

Another study evaluated the risk of diabetes mellitus in 2,264 5-year survivors of Hodgkin lymphoma (42% younger than 25 years at diagnosis) After a median follow-up of 21.5 years, the cumulative incidence of diabetes mellitus was 8.3% (95% CI, 6.9%–9.8%) for the overall cohort and 14.2% (95% CI, 10.7%–18.3%) for those treated with more than 36 Gy para-aortic radiation. Survivors treated with more than 36 Gy of radiation to the para-aortic lymph nodes and spleen had a 2.3-fold increased risk of diabetes mellitus compared with those who did not receive radiation. The risk of diabetes mellitus increased with higher doses to the pancreatic tail.[80]

In a report from the CCSS that compared 8,599 childhood cancer survivors to 2,936 randomly selected sibling controls, and after adjustment for age, BMI, and several demographic factors, the risk of diabetes mellitus was 1.8 times higher in survivors (95% CI, 1.3–2.5; P < .001). Significant associations were found between diabetes mellitus and young age at diagnosis (0–4 years), the use of alkylating agents, and TBI or abdominal radiation. Also, survivors were significantly more likely to be receiving medication for hypertension, dyslipidemia, and/or diabetes mellitus than were sibling controls.[81]

Fromm M, Littman P, Raney RB, et al.: Late effects after treatment of twenty children with soft tissue sarcomas of the head and neck. Experience at a single institution with a review of the literature. Cancer 57 (10): 2070-6, 1986. [PUBMED Abstract]

Raney RB, Asmar L, Vassilopoulou-Sellin R, et al.: Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive report from the Intergroup Rhabdomyosarcoma Studies (IRS)-II and - III. IRS Group of the Children's Cancer Group and the Pediatric Oncology Group. Med Pediatr Oncol 33 (4): 362-71, 1999. [PUBMED Abstract]